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Article: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition

TitleGenome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition
Authors
Issue Date2014
Citation
Cancer Cell, 2014, v. 25, n. 3, p. 393-405 How to Cite?
AbstractSmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n= 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant. © 2014 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/313961
ISSN
2023 Impact Factor: 48.8
2023 SCImago Journal Rankings: 17.507
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKool, Marcel-
dc.contributor.authorJones, David T.W.-
dc.contributor.authorJäger, Natalie-
dc.contributor.authorNorthcott, Paul A.-
dc.contributor.authorPugh, Trevor J.-
dc.contributor.authorHovestadt, Volker-
dc.contributor.authorPiro, Rosario M.-
dc.contributor.authorEsparza, L. Adriana-
dc.contributor.authorMarkant, Shirley L.-
dc.contributor.authorRemke, Marc-
dc.contributor.authorMilde, Till-
dc.contributor.authorBourdeaut, Franck-
dc.contributor.authorRyzhova, Marina-
dc.contributor.authorSturm, Dominik-
dc.contributor.authorPfaff, Elke-
dc.contributor.authorStark, Sebastian-
dc.contributor.authorHutter, Sonja-
dc.contributor.authorSxeker-Cin, Huriye-
dc.contributor.authorJohann, Pascal-
dc.contributor.authorBender, Sebastian-
dc.contributor.authorSchmidt, Christin-
dc.contributor.authorRausch, Tobias-
dc.contributor.authorShih, David-
dc.contributor.authorReimand, Jüri-
dc.contributor.authorSieber, Laura-
dc.contributor.authorWittmann, Andrea-
dc.contributor.authorLinke, Linda-
dc.contributor.authorWitt, Hendrik-
dc.contributor.authorWeber, Ursula D.-
dc.contributor.authorZapatka, Marc-
dc.contributor.authorKönig, Rainer-
dc.contributor.authorBeroukhim, Rameen-
dc.contributor.authorBergthold, Guillaume-
dc.contributor.authorVan Sluis, Peter-
dc.contributor.authorVolckmann, Richard-
dc.contributor.authorKoster, Jan-
dc.contributor.authorVersteeg, Rogier-
dc.contributor.authorSchmidt, Sabine-
dc.contributor.authorWolf, Stephan-
dc.contributor.authorLawerenz, Chris-
dc.contributor.authorBartholomae, Cynthia C.-
dc.contributor.authorVon Kalle, Christof-
dc.contributor.authorUnterberg, Andreas-
dc.contributor.authorHerold-Mende, Christel-
dc.contributor.authorHofer, Silvia-
dc.contributor.authorKulozik, Andreas E.-
dc.contributor.authorVon Deimling, Andreas-
dc.contributor.authorScheurlen, Wolfram-
dc.contributor.authorFelsberg, Jörg-
dc.contributor.authorReifenberger, Guido-
dc.contributor.authorHasselblatt, Martin-
dc.contributor.authorCrawford, John R.-
dc.contributor.authorGrant, Gerald A.-
dc.contributor.authorJabado, Nada-
dc.contributor.authorPerry, Arie-
dc.contributor.authorCowdrey, Cynthia-
dc.contributor.authorCroul, Sydney-
dc.contributor.authorZadeh, Gelareh-
dc.contributor.authorKorbel, Jan O.-
dc.contributor.authorDoz, Francois-
dc.contributor.authorDelattre, Olivier-
dc.contributor.authorBader, Gary D.-
dc.contributor.authorMcCabe, Martin G.-
dc.contributor.authorCollins, V. Peter-
dc.contributor.authorKieran, Mark W.-
dc.contributor.authorCho, Yoon Jae-
dc.contributor.authorPomeroy, Scott L.-
dc.contributor.authorWitt, Olaf-
dc.contributor.authorBrors, Benedikt-
dc.contributor.authorTaylor, Michael D.-
dc.contributor.authorSchüller, Ulrich-
dc.contributor.authorKorshunov, Andrey-
dc.contributor.authorEils, Roland-
dc.contributor.authorWechsler-Reya, Robert J.-
dc.contributor.authorLichter, Peter-
dc.contributor.authorPfister, Stefan M.-
dc.date.accessioned2022-07-06T11:28:37Z-
dc.date.available2022-07-06T11:28:37Z-
dc.date.issued2014-
dc.identifier.citationCancer Cell, 2014, v. 25, n. 3, p. 393-405-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/313961-
dc.description.abstractSmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n= 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant. © 2014 Elsevier Inc.-
dc.languageeng-
dc.relation.ispartofCancer Cell-
dc.titleGenome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ccr.2014.02.004-
dc.identifier.pmid24651015-
dc.identifier.pmcidPMC4493053-
dc.identifier.scopuseid_2-s2.0-84896096387-
dc.identifier.volume25-
dc.identifier.issue3-
dc.identifier.spage393-
dc.identifier.epage405-
dc.identifier.eissn1878-3686-
dc.identifier.isiWOS:000333233400015-

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